Epileptik Ensefalopati, Erken İnfantil Epileptik Ensefalopati Alt Tipleri ve Yeni Tanımlanan Nadir Epileptik Ensefalopatiler
Özet
Epileptik ensefalopatiler; dirençli nöbetler, ciddi EEG bozuklukları ve belirgin gelişimsel gerilik ile seyreden karmaşık ve heterojen hastalıklardır. Genetik temellerin, özellikle yeni nesil dizileme yöntemleriyle keşfedilen mutasyonların anlaşılması, patofizyolojik süreçlerin aydınlatılmasında kritik bir rol oynamaktadır. Hayvan modelleri, bu nadir ve ağır sendromların mekanizmalarını çözmek ve yeni tedavi stratejileri geliştirmek için vazgeçilmez bir araç sunmaktadır. Günümüzde tanımlanan çok sayıda alt tip için henüz özgül tedavilerin sınırlı olması, nörolojik gelişimi derinden etkileyen bu hastalıkların yönetimini zorlaştırmaya devam etmektedir.
Epileptic encephalopathies are complex, heterogeneous disorders defined by refractory seizures, severe EEG abnormalities, and significant developmental impairment. Understanding the genetic foundations—increasingly revealed through advanced sequencing—is essential for clarifying the underlying pathophysiology. Animal models provide vital insights into these rare conditions, serving as a basis for exploring mechanistic pathways and testing emerging therapeutic strategies. Despite progress in identifying numerous EIEE subtypes, effective targeted treatments remain limited, posing a continuous challenge for pediatric neurology.
Referanslar
Engel J. A Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy: Report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001;42: 796-803.
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE Classification of the Epilepsies Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4): 512–521.
Nieh SE, Sherr EH. Epileptic Encephalopathies: New Genes and New Pathways. Neurotherapeutics. 2014;11: 796–806.
Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain. 201 142(8):2303-2318.
Ehlers CL, Henriksen SJ, Wang M, Rivier J, Vale W, Bloom FE. Corticotropin releasing factor produces increases in brain excitability and convulsive seizures in rats. Brain Res. 1983;278: 332–336.
Weiss SR, Post RM, Gold PW, et al. CRF-induced seizures and behavior: Interaction with amygdala kindling. Brain Res. 1986;372: 345 –351.
Baram TZ. Pathophysiology of massive infantile spasms: Perspective on the putative role of the brain adrenal axis. Ann Neurol. 1993;33: 231-236.
Baram TZ, Mitchell WG, Snead OC III, Horton EJ, Saito M. Brain-adrenal axis hormones are altered in the CSF of infants with massive infantile spasms. Neurology. 1992;42: 1171–1175.
Baram TZ, Schultz L. ACTH does not control neonatal seizures induced by administration of exogenous corticotropin-releasing hormone. Epilepsia. 1995;36: 174–178.
Mares P, Velisek L. N-methyl-D-aspartate (NMDA)- induced seizures in developing rats. Brain Res Dev Brain. 1992;65: 185–189.
Kabova R, Liptakova S, Slamberova R, Pometlova M, Velisek L. Age-specific N-methyl-D-aspartate-induced seizures: Perspectives for the West syndrome model. Epilepsia. 1992;40: 1357–1369.
Stafstrom CE, Sasaki-Adams DM. NMDA-induced seizures in developing rats cause long-term learning impairment and increased seizure susceptibility. Epilepsy Res. 2003;53: 129–137.
Wang YJ, Zhang Y, Liang XH, Yang G, Zou LP. Effects of adrenal dysfunction and high-dose adrenocorticotropic hormone on NMDA-induced spasm seizures in young Wistar rats. Epilepsy Res. 2012;100: 125-131.
Velisek L, Jehle K, Asche S, Veliskova J. Model of infantile spasms induced by N-methyl-D-aspartic acid in prenatally impaired brain. Ann Neurol. 2007;61: 109–119.
Chachua T, Yum MS, Veliskova J, Velisek L. Validation of the rat model of cryptogenic infantile spasms. Epilepsia. 2011;52: 1666–1677.
Yum MS, Chachua T, Veliskova J, Velisek L. Prenatal stress promotes development of spasms in infant rats. Epilepsia. 2012;53: e46 –e49.
Romano C, Tine A, Fazio G, et al. Seizures in patients with trisomy 21. Am J Med Genet. 1990;7: 298–300.
Cortez MA, Shen L, WuY, et al. Infantile spasmsand Down syndrome: A new animal model.Pediatr Res. 2009;65: 499-503.
Frost JD Jr, Hrachovy RA. Pathogenesis of infantile spasms: A model based on developmental desynchronization. J Clin Neurophysiol.2005;22: 25-36.
Lee CL, Frost JD Jr, Swann JW, Hrachovy RA. A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia.2008;49: 298–307.
Frost JD Jr, Lee CL, Hrachovy RA, Swann JW. High frequency EEG activity associated with ictal events in an animal model of infantile spasms. Epilepsia.2011;52: 53–62.
Frost JD Jr, Lee CL, Le JT, Hrachovy RA, Swann JW. Interictal high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis.2012;46: 377–388.
Marsh E, Fulp C, Gomez E, Nasrallah I, et al. Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. Brain.2009;132: 1563–1576.
Price MG, Yoo JW, Burgess DL, et al. A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. J Neurosci.2009;29: 8752–8763.
McCarthy MM. Estradiol and the developing brain. Physiol Rev.2008;88: 91–124.
Olivetti PR, Maheshwari A, Noebels JL. Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome. Sci Transl Med.2014;6: 220ra212.
Lado FA, Moshe´ SL. Role of subcortical structures in the pathogenesis of infantile spasms: What are possible subcortical mediators? Int Rev Neurobiol.2002; 49: 115 –140.
Scantlebury MH, Galanopoulou AS, Chudomelova L, Raffo E, Betancourth D, Moshe´ SL. A model of symptomatic infantile spasms syndrome. Neurobiol Dis.2010;37: 604 – 612.
Silverstein F, Johnston MV. Cerebrospinal fluid monoamine metabolites in patients with infantile spasms. Neurrology.1984;34: 102–105.
Galanopoulou AS. Basic mechanisms of catastrophic epilepsy—Overview from animal models. Brain Dev.2013;35: 748 –756.
Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target. Epilepsia.2012b;53: 1119–1130.
Uhlmann EJ,Wong M, Baldwin RL, et al Astrocyte specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol.2002;52: 285–296.
Meikle L, Talos DM, Onda H, et al. A mouse model of tuberous sclerosis:Neuronal loss of Tsc causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci.2007;27: 5546–5558.
Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol.2007;61: 139–152.
EhningerD, Han S, Shilyansky C, et al. Reversal of learning deficits in a Tsc2þ/ – mouse model of tuberous sclerosis. NatMed. 2008;14: 843–848.
Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ,Wong M. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation ina mouse model of tuberous sclerosis complex. Hum Mol Genet.2011; 20: 445–454.
Fu C, Cawthon B, Clinkscales W, Bruce A, Winzenburger P, Ess KC. GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb Cortex.2012;22: 2111–2119.
Ljungberg MC, Sunnen CN, Lugo JN, Anderson AE, D’Arcangelo G. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Disease Model Mech.2009;2: 389 –398.
Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci.2009;29: 1773–1783.
Sunnen CN, Brewster AL, Lugo JN, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia.2011;52: 2065–2075.
Scantlebury MH, Gibbs SA, Foadjo B, Lema P, Psarropoulou C, Carmant L. Febrile seizures in the predisposed brain: A new model of temporal lobe epilepsy. Ann Neurol.2005;58: 41–49.
Pun RY, Rolle IJ, Lasarge CL, et al. 2012. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron.2012;75: 1022–1034.
Kellinghaus C, Kunieda T, Ying Z, Pan A, Luders HO, Najm IM. Severity of histopathologic abnormalities and in vivo epileptogenicity in the in utero radiation model of rats is dose dependent. Epilepsia.2004;45: 583–591.
Trotter SA, Kapur J, Anzivino MJ, Lee KS. GABAergic synaptic inhibition is reduced before seizure onset in a genetic model of cortical malformation. J Neurosci.2006;26: 10756–10767.
Galanopoulou AS, Moshe SL. Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: a view from preclinical studies. Neurobiol Dis.2015;79: 135-149.
Ohtahara S, Ishida T, Oka E. On the specific age dependent epileptic syndrome. No to Hattasu.1976;8: 270-280.
Pavone P, Spalice A, Polizzi A, Parisi P, Ruggieri M. Ohtahara syndrome with emphasis on recent genetic discovery. Brain Dev.2012;34: 459-468.
Feinberg AP, Leahy WR. Infantile spasms: case report of sex linked inheritance. Dev Med Child Neurol.1977;19: 524–526.
Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet.2006;43: 729–734.
Stromme P, Mangelsdorf ME, Shaw MA, et al. Mutations in the human ortholog of Aristaless cause X- linked mental retardation and epilepsy. Nat Genet.2002;30: 441-445.
Fullston T, Brueton L, Willis T, et al. Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p. Y27X). Eur J Hum Genet.2010;18: 157-162.
Kato M, Saitah S, Kamei A, et al. A longer polyalanine expansion mutation in the ARX gene causes early infantile epielptic encephalopathy with supression-burst pattern (Ohtahara syndrome). Am J Hum Genet.2007;81: 361-366.
Bhat SS, Rogers RC, Holden KR, Srivastava AK: A novel in-frame deletion in ARX is associated with lissencephaly with absent corpus callosum and hypoplastic genitalia. Am J Hum Genet A. 2005;138: 70-72.
Kato M, Das S, Petras K, et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat.2004; 23. 147-159.
Ichiba N, Yamatogi Y, Ohtahara S. Reappraisal of the treatment of age-dependent epileptic encephalopathy with ACTH. No To Hattatsu (Tokyo).1987;19: 90–97.
Ohtsuka Y, Amano R, Mizukawa M, Oka E, Ohtahara S. Treatment of intractable childhood epilepsy with high-dose valproate. Epilepsia.1992;33: 158–164.
Baxter PS, Gardner-Medwin D, Barwick DD, Ince P, Livingston J, Murdoch-Eaton D. Vigabatrin monotherapy in resistant neonatal seizures. Seizure.1995;4: 57–95.
Ozawa H, Kawada Y, Noma S, Sugai K. Oral high-dose phenobarbital therapy for early infantile epileptic encephalopathy. Pediatr Neurol.2002;26: 222–224.
Krsek P, Sebronova´ V, Procha´zka T, Maulisova´ A, Koma´rek V. Successful treatment of Ohtahara syndrome with chloral hydrate. Pediatr Neurol.2002;27: 388–391.
Ohno M, Shimotsuji Y, Abe J, Shimada M, Tamiya H. Zonisamide treatment of early infantile epileptic encephalopathy. Pediatr Neurol.2000;23: 341–344.
Nachanakian A, Hmaimess G, El- Helou A, Alaywan M, Adem-Hachem C, Kadhim H. Early modified functional hemispherectomy in a young infant with Ohtahara syndrome and hemimegalencephaly. J Child Neurol.2015;30: 522-526.
Wong TT, Kwan SY, Chang KP, et al. Corpus callosotomy in children. Childs Nerv Syst. 2006;22: 999–1011.
Hanefeld, F. The clinical pattern of the Rett syndrome. Brain Dev.1985;7: 320–325.
Kalscheuer V.M., Tao J., Donnelly A. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am. J. Hum. Genet.2003;72: 1401–1411.
Lin, C., Franco B., Rosner, M.R. CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. Hum. Mol. Genet.2005;24: 3775–3786.
Olson H.E., Demarest S.T., Pestana-Knight, et al. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: Clinical review. Pediatr. Neurol.2019;97: 18–25.
Fuchs C, Trazzi S, Torricella R, et al. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling. Neurobiol. Dis.2014;70: 53–68.
Scala E, Ariani F, Mari, F. CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J. Med. Genet.2005;42: 103–107.
Russo S, Marchi M, Cogliati F, Bonati M.T., Pintaudi M. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics.2009;10: 241–250.
Bahi-Buisson N, Villeneuve N, Caietta E. Recurrent mutations in the CDKL5 gene: Genotype-phenotype relationships. Am. J. Med. Genet. Part A 2012;158: 1612–1619.
Masliah-Plachon J, Auvin S, Nectoux J, Fichou Y, Chelly J, Bienvenu T. Somatic mosaicism for a CDKL5 mutation as an epileptic encephalopathy in males. Am. J. Med. Genet. Part A.2010; 152: 2110–2111.
Mangatt M, Wong K, Anderson B, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis.2016;11: 39.
Amin S, Majumdar A, Mallick AA. Caregiver’s perception of epilepsy treatment, quality of life and comorbidities in an international cohort of CDKL5 patients. Hippokratia.2017;21: 130–135.
Lilles S, Talvik IJ, Noormets K, Vaher U, Ounap K, Reimand T. CDKL5 gene-related epileptic encephalopathy in Estonia: Four cases, one novel mutation causing severe phenotype in a boy, and overview of the literature. Neuropediatrics.2016;47: 361–367.
Frullanti E, Papa F, Grillo E, et al. Analysis of the Phenotypes in the Rett Networked Database. Int J Genom.2019; 6956934.
Saitsu H, Osaka H, Nishiyama K, et al. A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5. Brain Dev.2012;34: 364–367.
Bahi-Buisson N, Bienvenu T. CDKL5-related disorders: From clinical description to molecular genetics. Mol Syndromol.2011;2: 37–152.
Fehr S, Wong K, Chin R. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology.2016;87: 2206–2213.
Fehr S, Downs J, Ho G, et al. Functional abilities in children and adults with the CDKL5 disorder. Am J Med Genet Part A.2016;170: 2860–2869.
Tang Y, Wang Z, Sarwar S, et al. Brain morphological changes in children with cylin-dependent-kinase-like-5 deficiency disorder. Eur J Pediatr Neurol.2011;31: 46-53.
Devinsky O, Verducci C, Thiele EA. Open-label use of highly purified CBD (Epidiolex(R)) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav.2018;86: 131–137.
Lim Z, Wong K, Olson HE, Bergin AM, Downs J, Leonard H. Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients. Epilepsia. 2017;58: 1415–1422.
Lim Z, Wong K, Downs J, Bebbington K, Demarest S, Leonard H. Vagus nerve stimulation for the treatment of refractory epilepsy in the CDKL5 Deficiency Disorder. Epilepsy Res. 2018;146: 36–40.
Trazzi S, De Franceschi, M Fuchs, et al. CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder. Hum Mol Genet.2018;27: 1572–1592.
Balestra D, Giorgio D, Bizzotto M, et al. Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy. Int J Mol Sci.2019;20: 4130.
Molinari F, Raas-Rothschild A, Rio M, et al. Impaired Mitochondrial Glutamate Transport in Autosomal Recessive Neonatal Myoclonic Epilepsy. Am J Hum Genet.2005;76: 334-339.
Xu Y, Ola MS, Berkich DA, et al. Energy sources for glutamate neurotransmission in the retina: absence of the aspartate/glutamate carrier produces reliance on glycolysis in glia. J Neurochem. 2007;101: 120–131.
Berkich DA, Ola MS, Cole J, Sweatt AJ, Hutson SM, LaNoue KF. Mitochondrial transport proteins of the brain. J Neurosci Res.2007;85: 3367–3377.
Milh M, Becq H, Villeneuve N, Ben-Ari Y, Aniksztejn L. Inhibition of glutamate transporters results in a ‘suppression-burst’ pattern and partial seizures in the newborn rat. Epilepsia.2007; 48: 169–174.
Molinari F, Kaminska A, Fiermonte G, et al. Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with supression bursts. Clinical Genetics.2009;76: 188-194.
Saitsu H, Kato M, Mizuguchi T, et al. De novo mutations in the gen encoding STXBP1 (MUNC18-1)cause early infantile epileptic encephalopathy. Nat Genet.2008;40: 782-788.
Wenk GL, Naidu S, Casanova MF, Kitt CA, Moser H. Altered neurochemical markers in Rett's syndrome. Neurology.1991;41: 1753–175
Mori A, Okuyama K, Horie M, et al. Alteration of methamphetamine-induced striatal dopamine release in mint-1 knockout mice. Neurosci Res.2002;43: 251–257.
Groffen AJ, Martens S, Diez Arazola R, et al. Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release. Science.2010;327: 1614–1618.
Rezazadeh A, Uddin M, Snead III OC, et al. STXBP1 encephalopathy is associated with awake bruxism. Epilepsy & Behavior.2019;92: 121–124.
Chen W, Cai ZL, Chao ES, et al. Stxbp1/Munc18–1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy. Elife.2020;9: e48705.
Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology.2016;86: 954–962.
Cortez L, Sim V. The therapeutic potential of chemical chaperones in protein folding diseases. Prion.2014;8: 197–202.
Guiberson NGL, Pineda A, Abramov D, et al. Mechanism-based rescue of Munc18–1 dysfunction in varied encephalopathies by chemical chaperones. Nature Communications. 2018;9: 3986.
Saitsu H, Kato M, Koide A, et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol.2012;72: 298–300.
Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet.1998;18: 25–29.
Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science.1998; 279: 403-406.
Numis AL, Angriman M, Sullivan JE, et al. KCNQ2 encephalopathy: Delineation of the electroclinical phenotype and treatment response. Neurology.2014;82: 368-370.
Kim H, Yang D, Kim S, et al. Clinical characteristics of KCNQ2 encephalopathy. Brain & Development.2021;43: 244–250.
Garin Shkolnik T, Feuerman H, Didkovsky E, et al. Blue-gray mucocutaneous discoloration: a new adverse effect of ezogabine. JAMA Dermatol.2014;150: 984–989.
Blanchard MG, Willemsen MH, Walker JB, et al. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet.2015; 52: 330-337.
Veeramah KR, O’Brien JE, Meisler MH, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet.2012;90: 502-510.
Sprunger LK, Escayg A, Tallaksen-Greene S, Albin RL, Meisler MH. Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3. Hum Mol Genet.1999;8: 471–479.
Kearney JA, Buchner DA, De Haan G, et al. Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). Hum Mol Genet.2002;11: 2765–2775.
Estacion M, O'Brien JE, Conravey A, et al. A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy.Neurobiol Dis.2014; 69: 117–123.
Wagnon JL, Korn MJ, Parent R, et al. Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Hum Mol Genet.2015;24: 506– 515.
Edvardson S, Baumann AM, Muhlenhoff M, et al. West syndrome caused by ST3Gal-III deficiency. Epilepsia.2013;54: e24–e27.
Taniguchi A, Saito K, Kubota T, Matsumoto K. Characterization of the promoter region of the human Gal-beta-1,3(4) GlcNAc alpha-2,3-sialyltransferase III (hST3Gal III) gene. Biochim Biophys Acta.2003;1626: 92-96.
Sturgill ER, Aoki K, Lopez PH, et al. Biosynthesis of the major brain gangliosides GD1a and GT1b. Glycobiology.2012;22: 1289–1301.
Harduin- Lepers A, Vallejo- Ruiz V, Krzewinski- Recchi MA, Samyn- Petit B, Julien S, Delannoy P.The human sialyltransferase family. Biochimie.2001;83: 727-737.
Kono M, Ohyama L, Lee YC, Hamamoto T, Kojima N, Tsuji S. Mouse beta-galactoside alpha 2,3-sialyltransferases: comparison of in vitro substrate specifities and tissue specific expression. Glycobiology.1997;7: 469-479.
Ellies LG, Sperandio M, Underhill GH, et al. Sialyltransferase specifity in selectin ligand formation. Blood.2002;100: 3618-3625.
Hu H, Eggers K, Chen W, et al. ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet.2011;89: 407-414.
Kiwamoto T, Brummet ME, Wu F, et al. Mice deficient in the St3gal3 gene product alpha2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation. J Allergy Clin Immunol.2014;133: 240–247.
Nakamura K, Kodera H, Akita T, et al. De novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am J Hum Genet.2013;93: 496–505.
Marce-Grau A, Dalton J, Lopez-Pison J, et al. GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females. Orphanet J Rare Dis 2016;11: 38.
Kehrl JM, Sahaya K, Dalton HM, et al. Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)? Mamm Genome.2014;25: 202–210.
Kelly MC, Park M, Mihalek I, et al. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region. Epilepsia.2019;60: 406–418.
Frankel WN, Yang Y, Mahaffey CL, Beyer BJ, O'Brien TP. Szt2, a novel gene for seizure threshold in mice. Genes Brain Behav.2009;8: 568–576.
Basel-Vanagaite L, Hershkovitz T, Heyman E, et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet.2013;93: 524–529.
Trivisano M, Rivera M, Terracciano A, et al. Developmental and epileptic encephalopaty due to SZT2 genomic variants: Emerging features of a syndromic condition. Epilepsy Behav,2020;108: 107097.
Novara F, Rizzo A, Bedini G, et al. MEF2C deletions and mutations versus duplications: a clinical comparison. Eur J Med Genet.2013;56: 260–265.
Bi W, Drake CJ, Schwarz JJ. The transcription factor MEF2C-null mouse exhibits complex vascular malformations and reduced cardiac expression of angiopoietin 1 and VEGF. Dev Biol. 1999;211: 255–267.
Li H, Radford JC, Ragusa MJ, et al. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A.2008; 105: 9397–9402.
Borlot F, Whitneya R, Cohn RD, Weiss S. MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review. Seizure: European Journal of Epilepsy.2019;67: 86-90.
Kono M, Ohyama Y, Lee YC, Hamamoto T, Kojima N, Tsuji S. (1997) Mouse beta-galactoside alpha 2,3-sialyltransferases: comparison of in vitro substrate specificities and tissue specific expression. Glycobiology 7:469–479.
